Efficacy and Safety of Cyclosporin
`Ophthalmic Emulsion in the Treatment
`of Moderate-to-severe Dry Eye Disease
`
`Dose-Ranging Randomized Trial
`
`Dara Stevenson MD1 Joseph Tauber MD2 Brenda
`
`Reis PhD The Cclosporin
`
`Phase
`
`Study Group
`
`To investigate the efficacy safety formulation tolerabllty and optmal dosmg of
`novel cyclo
`Objective
`oikn-water emulsion formulation for the treatment of moderate-to-severe dry eye thsease
`sporin
`Design Randomized mufticenter double-masked paraflel-group dose-response controfled triaL
`Total enroflment 162 patients cyclosporin
`groups 129 patients vehicle group 33 patients
`Participants
`ophthalmic emulsion 005% Oi
`02% or
`Intervention
`Patients instilled study medication cyclosporin
`OA% or vehicle twice daily into both eyes for 12 weeks followed by
`4-week posttreatment observation period
`Main Outcome Measures Efficacy
`rose bengal staining superficial punctate keratitis Schirmer tear test
`symptoms of ocular discomfort and the Ocular Surface Disease Index OSDI
`measure of symptom frequency
`blood levels conjunctival
`and impact
`on vision-related
`functioning Safety biomicroscopy cyclosporin
`microbiology intraocular pressure visual acuity and monitoring of adverse events
`sicca the most significant
`Results
`subset of 90 pattunts with moderate-to-severe keratoconjunctivitis
`In
`treatment were
`rose bengal staining superficial punctate keratits sandy or
`improvements with cyclosponn
`gritty feeling dryness and itching with improvements persisting into the posttreatment period in some treatment
`decrease in OSDI scores indicating
`groups There was also
`decrease
`the effect of ocular symptoms on
`01
`produced the most
`patients daily lives There was no clear dose-response
`relationship but cyclosporin
`005% gave the most
`and subjective end points and cyclosporin
`improvement
`consistent
`objective
`in patient symptoms The vehicle also performed well perhaps because of
`improvement
`consistent
`its long
`residence time on the ocular surface There were no significant adverse effects no microbial overgrowth and no
`increased risk of ocular infection in any treatment group The highest cyclosporin
`blood concentration detected
`was Oi
`ng/mL All treatments were well tolerated by patients
`02% and 04% were safe and well
`ophthalmic emulsions 005% Ui
`Conclusions Cyclosporin
`tolerated sgnficantly improved the ocular signs and symptoms of moderate-to-severe dry eye disease and
`005% and Di
`were deemed
`decreased the effect of the disease on vsion-related functoning Cyclosporin
`the most appropriate formulations for future clinical studies because no additional benefits were observed with
`
`the higher concentrations Ophrhalmology 2000 2000 by the American Academy of Ophthal
`
`mology
`
`ey dis
`sun eys indicate that dry
`Recent population-based
`ease or keratoconjunctivitis sicca affects millions of people
`as 17% to 25% of
`\%orldnide.l8 Moreo\er
`as many
`
`Osigmally ieceised May
`January 27 2000
`ccepted
`
`1999
`
`Manuscript no 99216
`
`s1eres Hospitcl Professioncl Buildmg Nev Orleans Louisiana
`
`2Kansas City Missouri
`
`3Allergan Inc Irvine California
`
`Reprint requests to Linda Lessis 375 Anton Boulevard Suite 900 Costa
`Mesa
`92626
`
`Prelmi.inar
`
`at the annual meeting of
`results of this study
`crc presented
`Fort Lauder
`ision and Ophthalmology
`the \nsociation
`for Research in
`dale Florida May 1997 and at the LIth Coness of the Furopean SocietI
`of Ophthalniolog Budapest Hungary June 1997
`
`Supported by
`
`grant
`
`from Mlergan Inc
`
`patients visiting ophthalmic clinics report dry eye syrup
`the most common
`toms making dis eye disease one of
`complaints seen by ophthalmic specialists Patients with dis
`eve disease typically complain of syniptonis of ocular dis
`comfort
`dry gritty
`feeling often accompanied
`including
`on the duration and
`by foreign body sensation Depending
`severit of disease damage to the ocular surface may also
`have
`be present Patients wiih chronic uncontrolled dry
`and are more likeh
`an increased risk of ocular infections56
`
`to have ocular
`infections
`that progress to endophthalmitis.7
`growing body of evidence suggests that chronic dry
`result of an underlying cytokine
`and
`eye disease is the
`inflammatory process thai affects the lac
`receptor-mediated
`ritual gland acini and ducts leading to abnonnalities in the
`tear film and ultimately disrupting the homeostasis of
`the
`Most con\entional
`ocular surface.8
`treatments
`for dry
`
`2000 by the American
`
`\eademv
`
`of Ophthalmc logs
`
`Published by Else 1er Science Inc
`
`tSSN 161 n420 00
`
`see front matter
`
`967
`
`PIt SOl 61-64200000035-X
`
`FAMY CARE - EXHIBIT 1015-0001
`
`

`

`Ophthalmology
`
`Volume 107 Number
`
`May 2000
`
`to
`
`instill
`
`topical
`
`that
`
`eye disease focus on tear replacement or tear preservation
`these processes How es er
`and are incapable of affecting
`do
`treatment with the inimunomodulatoiy agent
`has been shown to reduce cell-mediated inflam
`sporin
`mators responses associated with inflammatory ocular sur
`face diseases.23 Preliminar
`studies has
`demonstrated
`treatment with topical
`c\closporin
`can result
`that
`in
`improvement of the signs and symptoms of dry eye disease
`Invest Ophthalmol Vis Sci 199637Suppl
`Foulits et al
`S646 Helms ci dl
`Invest Ophthalmol Vis Sci 199637
`Suppi S646.24
`In addition several studies have es
`tablished the efficacy of topical cyclosporin
`in the treat
`inent of keratoconjunctis
`itis sicca in dogs
`These find
`may pros ide
`ings suggest
`topical cvclosporin
`unique opportunity to move be ond treatments
`that onh
`alleviate the symptoms of thy eye disease to therapies that
`the inflammatory processes contributing to
`effectis ely target
`disease pathogenesis
`The purpose of this study was to investigate the efficacy
`tolembility and oplinial dosing of
`novel
`safety patient
`oil-in-water emulsion formulalion for the
`
`crc drv eye disease with or
`
`cs closporin
`treatment of moderate-lo-ses
`
`ssithoiit Sjogrens syndrome
`
`Methods
`
`Study Protocol
`
`This report describes
`
`randomized multicenter double-masked
`study The protocol was composed
`dose-response
`paiallel-group
`12-week
`of three phases
`2-week washout phase
`treatment
`phase This study was con
`and
`4-week
`phase
`posttreatrnent
`review board regula
`ducted in compliance with the institutional
`regulations sponsor and ins estigator ob
`tiois informed consent
`and the Declaration of helsinki Written infonned
`ligations
`consent was obtamed from all patients before the inthation of an
`study medication or study-related procedure
`Patients were recruited between Ma 1995
`Study Population
`1996 from mae clinical sites throughout
`and Februars
`the United
`least 21 ears of age and had
`Stales Fhgible patients were at
`diagnosis of keratoconj unctivitis sicca with or is ithout Sj Ogren
`ndromne refractor
`to conventional management Inclusion crite
`ria included Schirmer test without anesthesia of mm/S minutes
`in at least one eye mild superficial punctate keratitis defined as
`fluorescein
`score of
`conical punctate
`in either eye
`staining
`scak
`and one or more moderate
`dis eyerelated symptoms including itching burning blurred
`vision foreign hod sensation dryness photophobia and soreness
`oi pain Both eyes were treated but both eyes were not
`included in
`all anal ses see Statistical Methods
`Patients were excluded from stud participation if
`ocular disorder including ocular injury mfection non-dry
`eye
`inflammation trauma or surgery within the prior months
`ocular
`treatment that could interfeie with in
`were receising concurrent
`terpretation of the study results had an uncontrolled sy stemnic
`lactating or con
`disease or significant illness or were pregnant
`pregnancy
`sidering
`used in this studs were
`The medications
`Study Medications
`005% 1% 2%
`umt dose vials of unpreserved
`cyclosporin
`and 0.4% ophthalmic emulsion unit dose vials of unpreserved
`and RF
`2% ophthahnic
`einulsioir
`chicle for cyclosporin
`drops Allei gan Irs inc CA The sehicle for
`FRESH lubricant ci
`
`to
`
`thes had ani
`
`968
`
`emulsion is for
`each concentration of cyclosporm
`ophthahnic
`mulated slightly dilTerently because greater oil content
`is required
`of the active ingredient The
`to dissolve the higher concentrations
`2% ophthalmic emulsion hereafter
`chicle for cyclosporin
`referred to as iehicle was chosen for the control because it was
`used
`near the middle of the range of ci closporin
`concentrations
`Study Treatments During the washout
`phase patients were
`topical ophthalmic medications
`instructed to discontinue
`use of all
`except for REFRESh
`During this time the were instructed to use
`REFRESH minmnuin of four hut no more thai eight
`times daily
`the washout
`in each eye Patients
`svho
`completed
`successfully
`phase weme then given their assigned medication cyclosporin
`0.05% 0.1% 0.2% or 0.4% ophthalmic emulsion or emulsion
`and instructed
`their medication twice
`vehicle
`daily
`morning mid evening in both eyes for 12 weeks
`The use of
`REFRESH up to eight
`times daily in each eye was allowed
`during the treatment phase
`Outome Measures The efficacy measures is eme rose bengal
`scale from
`none to
`staining graded on
`severe
`superficial punctate keratit is measured
`at nasal
`temporal pupil
`and inferior and the scores summed each graded on
`scale from
`severe Schirmer tear
`none to
`test without anesthesia
`with nasal stimnulation only if needed to determine that
`the patient
`to secrete tears symptoms of ocular discom
`had some capacity
`scale from
`fort graded by investigator quenes on
`none to
`and in patient diaries on
`scale from
`no
`very severe
`discomfort
`discomfort
`interferes with nonnal daily
`to
`that
`scale of
`none to
`activity tear film debris graded on
`ci ses crc tear breakup timne and the lrequency and amount of
`REFRESH used
`in addition patient
`response to treatment was evaluated using
`the Ocular Surface Disease Index OSDI
`ulobal assessment
`consisting of 12 questions designed to assess the symp
`parameter
`toms of ocular irritation consistent with dry cy
`disease and their
`impact on vision-related functioning The questions
`triggers and
`areas ocular sy mptoins enviromunental
`ision-related
`function Each question is as phrased in terms of frequency how
`symptom how often they experienced
`often they were aware of
`difficuhts with
`specific task because of their symptoms etc and
`never and
`all
`scale from to where
`graded on
`the
`timne Patient
`responses to all answers were then combined for
`composite OSDI score ranging from to 100
`Treatment
`safety was assessed by biomicroscopy measurement
`hema
`blood leiels
`of ciciosporin
`conjunctival microbiology
`tology and blood chemistry panels intraocular pressure by appla
`96% contiast Regan
`and visual acuity
`by
`nation
`tonometly
`the study patients were moni
`letter Acuits Chart Throughout
`tored for signs and
`mptomns of adverse ci ents and formulation
`tolerability Any reported adverse event was graded by the inves
`for severity mild moderate or severe and assessed for
`tigator
`relationship to the study treatment none unlikely possible prob
`able definite or unknown
`and 12 during the
`at weeks
`Patients were ci aluated
`phase Dining these visits patients were ci aluated hr
`treatment
`changes from baseline in Schmner tear
`test rose bengal staining
`superficial punctate keratitis scores symptoms of ocular discom
`fort biomicroscopy and visual acuity After the completion of the
`patients were also evaluated
`phase
`at posttreatment
`treatment
`and During both yisits patients were assessed for Schinuer
`weeks
`tear
`test rose bengal staining superficial punctate keratitis ocular
`symptoms of discomfort biomicroscops and visual acuity
`Whole blood was obtained from all patients for evaluation of
`and
`cyclosporm trough les els at baseline treatment
`is ceks
`week
`iveek 12 additional blood
`12 and posttreatmcnt
`At
`samples were drawn at one study site only for evaluation of peak
`For evaluation
`of
`concentrations
`cclosporin
`levels
`
`covered three
`
`trough
`
`FAMY CARE - EXHIBIT 1015-0002
`
`

`

`Stevenson et al Cclosporin
`
`in Treatment of Dry Eye Disease
`
`blood was drawn immediately before the morning dose of study
`medication for ci aluation of peak levels blood was drawn
`and
`hours after mstillation of the final dose of study medication
`atiseek 12
`to the Ailergan Pharmacokinetics
`Blood samples were
`sent
`ahoratory where they were assayed by
`liquid chroinatography
`spectroscopy LC-MS/MS with
`dctcc
`mass spectroscopy/mass
`ng/ml One milliliter of human blood was acidified
`lion limit of
`with ml of ft
`IIC1 solution and anal\ tes extracted unth ml
`of meth tbut ether After separation from the acidified aqueous
`NaOH
`the orgamc lai er was made basic with ml of 0.1
`lai er
`centrifuged and the organic
`The
`extract was then evaporated
`200 1il of mobile phase
`and
`dried extract was reconstituted
`11 v/in and 100 p.l was injected mto the LC-MS/MS system The
`LC-MS/MS analy sis was conducted on PE-Sciex API Ill
`quadrnpole mass spectrometer Perkm Flmer Norwalk CT cou
`system Columbma MD Chromatog
`Shimadvu HPT
`pled to
`Key stone BDS Hypersil C8 column
`raphy was performed on
`mm j.m with
`50
`ammonium
`bmars mixture of
`acetate/0.4% Ionnic acid in water mobile phase
`and mmolIl
`ammonium acctate/0.4% formic acid in acetonitrile mobile phase
`.umder gradient elution The HET
`flow rate of 300
`effluent
`j.dlmin was split with 75
`directed
`to the atmospheric
`1.d/min
`ionization soul cc The mobile phase was 60% atO to 0.5 minute
`increased linearh to 9S% at minute held at 95% from to
`2.5 minutes and then decreased to 60% at minutes held
`was used as the mternal standard
`minutel Cy closporin
`softw are PE-Sciex Instruments Con
`The PE-Sciex MacQuan
`coid Ontario Canada was used to determine
`peak areas of
`analvte and internal standard peak area ratios of analyte/internal
`concentrations of un
`standard calibration curves and calculated
`and precisiun of thc LC-MSJMS method
`knowns
`he accuracy
`was assessed within each run using quality control blood samples
`and
`ng/ml The intradar accuracy percent ratio of
`at 0.1 0.2
`observed to nommal concentration ranged flomn 100% to 109%
`with precision coefficient of iariation ranging from 3% to 10%
`The interday accuracy ranged from 102% to 11 3% with precision
`ranging between 1% and 13%
`At
`four selected study centers ocular samples for microbio
`logic evaluation were collected from the conjunctival cul de sac at
`baseline treatment week 12 and posttreatnient week
`and sent to
`laboratory for culture and organism identification
`centralized
`from subjective mea
`Statistical Methods Efficacy variables
`on both
`es were analyzed
`stmnanents with data
`collected
`by
`averaging the data from both eves Efficacy
`variables from objec
`try measurements with data collected on both eves were analy zed
`using data from the worse eye The worse eye was defined as the
`ialue and the worse
`eye with the worse Schinner
`superficial
`punctate keratitis value pupil and nasal areas only at baselme
`of patient disease profiles sub
`Because of the heterogeneity
`group analyses of patients who had various
`degrees of disease
`anali zed separately Only patients with moderate
`ser eriti
`disease at baseline were included in the efficacy
`to-severe dry ci
`analysis described in this report All patients who received studs
`medication were included
`in the analysis of safcty variables
`parameters were summarized with descriptive
`Demographic
`and frequency
`tables Efficacy
`parameter
`comparisons
`analy 7ed with the Kruskal-Wallis
`among treatment groups
`wem
`between treatment groups were ana
`test Pairw se comparisons
`lyzed with the Wilcoxon rank sum
`test Within-group changes
`froni baseline were evaluated with the Wilcoxon signed-rank
`RLFRESII use intraocular pressure and laboratory variables were
`from
`analysis of variance Within-group changes
`analyzed
`by
`baseline were evaluated with the paired test Adverse event data
`two-sided test with
`were summarized by frequency
`tables
`005 was considered
`statmsticalh significant for all main effects
`
`triple
`
`test
`
`em
`
`statistics
`
`The null hypothesis was that
`there were no differences among
`the treatment groups with regard to changes from baseline values
`fhe alternative
`there was
`hypothesis was that
`change
`Power was calculated
`to detect an among-group difference
`in
`alues at week
`change from baseline in categon7ed Schinner tear
`For
`sample size of 12 to 15 patients in the moderate-to-severe
`standard error of0.394 and standard deviation
`subgroup analysis
`of 0.881 the power to detect
`one grade difference was 0.69
`
`Patient Treatment Assignment
`
`Qualified patients within each investigators population were as
`sigimed equally to one of the five niasked treatmnent groups sequemi
`randomization schedule geneiated by the
`to
`tially corresponding
`block of five design
`sponsor and using
`
`Study Masking
`
`All
`
`box was coded with
`
`study medications were liquids of similar appearance dis
`tw 0-com
`imit dose vials sealed
`pensed in identical
`idcntical
`identical boxes of 16
`and packed mu
`pouches
`partment plastic
`pouches each Each pouch and packing
`shipment number and the patient number
`When each box was dispensed
`the tear-off portion of the label
`was attached to the patients case report form If necessary be
`the an estigator
`serious or severe adverse es cut
`cause of
`could
`inevem sibly ummask the tear-off portion of the patient medication
`to detemmme which study medication the patiemmt had receis ed
`label
`patient care
`
`to institute appropriate
`
`Results
`
`pilot
`
`trial conducted with this new
`Because this was the first clinical
`formulation it was designed to function as
`cvclosporin
`patients who
`for future investigations Therefore
`varied
`study
`widely in the severity of their dry eye were enrolled The data from
`all patients who received
`study medication intent-to-treat popu
`lation were analyzed Howes er
`subgroup
`revealed
`analysis
`sizable population of patients who had moderate-to-severe
`dry eye
`dry eye disease was de
`disease at baselme Moderate-to-severe
`Schmnner tear test mm/S minutes at baseline in at least
`and superficial punctate keratitis pupil and nasal average
`one ey
`of 1.5 averaged oser both eyes Because these patients iepieseut
`for any dry eye tm eatment
`the
`the gm eatest
`therapeutic
`challenge
`of
`analysis presented here is confined
`to the evaluation
`This subgroup also represents
`this muoderate-to-ses crc subgroup
`the most appropriate target population for future clinical studies of
`dry eye themapeutics because these patients have sufficient main
`festations of the disease to allow the response
`to them apeutic
`inters ention to be more objectis ely evaluated Data from all pa
`tients were included
`the safety analysis
`
`fined as
`
`efficacy
`
`Participant Flow and Followup
`
`total of 162 patients was enrolled 129
`the cyclospormn
`groups and 33 in the vehicle group Table
`Eight patients were
`for administrative reasons Of the four patients dis
`discontinued
`continued because of ads erse ci emits two were in the velucle group
`one with
`and ocular burning and one with
`visual disturbance
`conjunctivitis and
`irritation dcnnatitis one was in the
`contact
`0.2% group ocular burrung and one was in the
`4% group myocardial
`infarction Only the ocular
`cy closporin
`ads cisc ci emits were considemed to be possibly or probably related
`to the study medication
`
`cyclospormn
`
`969
`
`FAMY CARE - EXHIBIT 1015-0003
`
`

`

`Ophthalmology
`
`Volume 107 Number
`
`May 2000
`
`Table
`
`Patient Disposition
`
`Trearrnenr
`
`tiro4
`
`Vehicle
`Cs.A005
`CsA 01cc
`CsA 0.2c
`CsA 0.4c
`
`Total
`
`Moderate-to-Severe Dry E1e Disease
`90
`
`Intent-to-Treat
`Population
`162
`Total Enrollment
`
`Completed
`
`Discontinued
`
`tomplered
`
`Discontinaed
`
`e0
`
`1000
`
`1000
`
`94.7
`
`100.0
`
`94.4
`
`97.8
`
`17
`
`18
`
`20
`
`17
`
`68
`
`00
`00
`
`5.3
`
`0.0
`
`is
`
`30
`
`30
`
`30
`
`28
`
`2.2
`
`150
`
`00
`
`099
`
`96.8
`
`9.8
`
`94.1
`
`67.5
`
`92.6
`
`12
`
`0e
`
`91
`
`32
`
`6.3
`50
`
`12
`
`7.4
`
`CsA
`
`cvclospoitn 5.
`
`Of the 90 patients with moderate-to-severe
`dD eye disease
`16
`0.05% group 19
`vi crc in the vehicle group 17 in the cyclosporin
`2%
`0.1% group 20 in the c9closporin
`the cyclosporin
`04% group One patient
`group and 18 in the
`closponn
`in the
`0.1% group was discontinued
`reasons
`for personal
`exciosporin
`04% group was discontinued
`and one patient
`in the
`closporin
`infarction same patient
`because of myocardial
`as mentioned
`earlier No patients medications
`were
`unmasked during this
`
`study
`
`Patient Demographics
`
`antibodies
`
`greater
`
`scores than
`022 and
`
`cvclosporin
`
`Significant
`
`rose bengal
`2% at all
`
`cvclosporin
`
`visits
`
`treatment vieck
`
`and 12
`
`treatment groups Significant improvements from baselme in tem
`rose bengal stainmg scores were observed Vs dli
`poral conjunctival
`1% at all
`treatment and posttrcatment
`cyclosporm
`vicits
`0.2% at week
`0.016 with
`12 and both posttreat
`closporin
`-z 0.047 with cvclosporinA 0.4% at week
`meat visits
`0.03 and with the emulsion vehicle at week 12
`0.047 Fig
`1% produced significant
`Cyclosporm
`improie
`ments in temporal conjunctival
`rose bengal staining
`0.05%
`0.006
`csclosponn
`vehicle
`04%
`0.007 at posttmeatment week
`improvements from baseline in nasal conjunctival
`observed with cyclosponn
`scores were
`staining
`0.022 with
`treatment and posttreatment
`0.1% and 0.05% at
`through
`4%
`week
`0.0311 in the cyclospormn
`posttreatment
`group at posttreatment week
`0.031 and in the vehicle
`0.025 There weie no
`treatment weeks
`group at
`in the change from baseline in
`significant among-group differences
`rose bengal staining
`nasal conjunctival
`At baselme mean
`scores for superficial punetate
`to 1.9 mall treatment groups Cclosporm AU 1%
`ranged from
`produced
`improvenient
`the greatest
`froni baseline in superficial
`and posttreat
`keratitis scores throughout
`the treatment
`meat periods range 0.9 to
`1.4 units Fig
`With the excep
`05% concentration
`treatment week
`tion of the
`12 and post-
`at
`from baseline
`irnproi ements
`significant
`superficial punctate keratitis were seen in all cyclosporin
`
`keratitis
`
`in
`
`treat
`
`punctate
`
`treatment
`
`vi eels
`
`Week
`
`Week
`
`Week
`
`12
`
`Post-Tx Wk
`
`Post-Tx Wk
`
`tO 06
`
`Cs
`
`CO
`
`Ce
`
`-itt
`
`-1.0
`
`1.2
`
`DVehcIe
`
`tCaAO05% CsAO.1% R1ICsAO.2%
`
`CsA0.4%
`
`Figure
`
`Change
`
`from baseline
`
`in temporal
`
`Cclosporin
`Signilcantly
`Significantly different from vehicle cyclosporin
`04c
`0.022
`
`different
`
`rose bengal staining CiA
`0047
`from baseline
`if
`005c and cyclosporiri
`
`fhc demographic
`of
`characteristics
`the patient population arc
`the mean patient age was approximatei5
`listed in Table
`Note that
`ears that more than 80% of patients were women and that
`58
`approximately 90% were white Approximately 32% of the pa
`tients in the moderate-to-severe dr eye group were also Sjogrens
`syndrome patients Sjogrcns syndrome was defined as the pres
`ence of one or more of the following in the blood antinuclear
`rheumatoid factor 30 international umts
`ml SjOgrens syndrome 10 112/mI or
`lU/nil anti
`bodies No significant differences were noted among the treatment
`dU eye
`groups for either the intent-to-treat or moderate-to-severe
`populations
`
`titer
`
`Efficacy Analysis
`
`At baseline mean scores for conjunctival
`rose bengal
`staining
`ranged fioin 1.2 to 20 for both temporal and nasal regions in all
`
`Table
`
`Patient Dernographmcs
`
`Moderate-to-Ses.ere
`
`Intent-to-Treat
`
`Dry Eye Disease
`90
`
`Population
`162
`
`58
`
`1SiC
`
`59 iSli8l
`
`17 189
`
`82
`
`t44t
`100
`i44
`
`26
`16
`
`145
`
`12
`
`1601
`iC40
`
`1895
`741
`0.o
`2.5
`
`120.5
`
`Age
`Mean Irange
`
`Cender 61
`Male
`
`Fcrnok
`
`Race Ci
`White
`
`Black
`
`Asian
`
`llispaoic
`
`Stôgrens syndrome in
`
`29 1i22
`
`CiA cvclosporas
`
`NA
`
`data riot available
`
`970
`
`FAMY CARE - EXHIBIT 1015-0004
`
`

`

`Stevenson et al
`
`Cyclosporin
`
`in Treatment of Dry Eye Disease
`
`Week
`
`12
`
`Post-Tx Wk
`
`Post-Tx Wk
`
`Week
`
`Week
`
`Week
`
`12
`
`Post-Tx Wk
`
`Post-TxWk
`
`xc
`
`cIt
`
`Is
`
`C-
`
`1.01
`
`0.5
`
`0.0
`
`-0.5
`
`-1.0
`
`1.5
`
`Vehicle
`
`PsA 0.06% CsA 1%
`
`111 CsA 0.2% in CsA 0.4%
`
`OVehiole
`
`TCsA0.05%
`
`CsAO.I% mnCsAO.2%
`
`inCsAO.4%
`
`Significantly different
`from vehicle
`
`candy different
`
`cyclosporin
`
`0.2o
`
`0.037
`
`in sandy or gritty feeling CsA yclo
`0.039
`from baseline
`
`signifi
`
`0.027
`
`significantly different
`
`from
`
`Figure
`
`Change
`
`from baseline
`
`Cyclosporiri
`
`Significantly different
`
`in superficial punctate
`from baseline
`
`keratitis CsA
`0.018
`
`Figure
`
`sporin
`
`Change
`
`from baseline
`
`ment groups at all
`time points dunng the 2-neck treatment phase
`012 and 4-neck posttrcatment period
`0.018 Sig
`fP
`keratitis was also
`impros ement
`nificant
`in superficial punctate
`observed iii patients treated with chicle at treatment weeks
`and
`12 and posttreatment week
`0.041 No statistically
`icant among-group differences
`in superficial punctate
`re observed
`values
`Baseline values for Schirmer tear
`test
`citing scores ranged
`from 24 to
`groups The most consistent
`treatment
`group with mean
`improvements were in the
`closporin
`mm at
`nun at week
`and
`increases in wetting length of
`neck 12 but
`these increases onh approached
`signifi
`seek 12
`came sseek
`The unl
`0.055
`0.05l
`significant impros emcnt
`from baseline occurred in the
`treatment week
`0.4% gmoup at
`0.008 and
`1P
`cyclosporin
`posttreatmnent week
`significant womsen
`0.023 whereas
`3.0 mm
`mg occurred in the vehicle group at week
`047
`04% produced
`025 greater
`Csclosporin
`significanth
`in Schirmer tear
`improvements from baseline
`test
`results
`than
`2% at posttreatment neck
`either vehicle or cyclosporin
`Symptoms of ocular di scom fort were evaluated from scheduled
`visit queries from the clinical
`ins estigator and from self-adminis
`tered weekl
`mptom results
`patient diaries Baseline
`suggest
`that patients may have consistently
`the seventy of
`underreported
`from the health
`their symptoms rshcn responding
`to the query
`professional compared with what
`they recorded
`Therefore onl
`symptom data from
`diaries using the
`patient
`entries inimcdiatelr before each scheduled visit are presented
`At baseline the mean score for sand or gmitt
`feeling ranged
`from .7 to
`treatment groups lhere
`mild to moderate in all
`from baseline in sands or grins
`significant improvement
`05% and 04% groups at several
`the cyclosporin
`0.039 Fig 3. At ticafinent week 12 all cyclosporin
`visits
`treatment groups had signfficantl
`impiovements in
`greater
`04 This
`sandy or gritt
`feeling than the vehicle group
`from vehicle was also seen at postlrcalment
`significant difference
`week
`05% and 0.4% groups
`0.006
`the csclosporin
`and at posttrcaflnent week
`0.05% 0.2% and
`in the cyclosporin
`week
`0.4% groups
`0.027 At posttreatment
`05% groups also demonstiuted
`0.4% and
`02% group
`than the
`closporin
`
`in all
`
`statisticall\
`
`as
`
`feeling
`
`sporin
`
`signif
`
`keratitis
`
`statistical
`
`in their diaries
`
`the cyclo
`
`significantlr
`
`imnproseinent
`
`greater
`0037
`At baseline the mean score for ocular dryness ranged from 2.3
`to 2.7 fmoderate
`to severe in all
`treatment groups Significant
`improvements from baseline in ocular dryness were seen at two or
`more time points in all cyclosporin
`the cyclo
`groups e1cept
`At posttreatment week
`0.1% group
`036 Fig
`
`sporin
`
`cyclosporin
`
`significantly greater
`
`itching
`
`0.05% 02% and 0.4% gioups all demonstrated
`inipros ements in ocular dryness than did the
`0.010
`sehicle group
`At baselme the mean score for ocular
`itching ranged from 1.4
`to 1.9 mild to moderate in all
`treatment groups Sigmficant
`improvements from baseline
`crc seen at one or
`ocular
`more time points in all of the
`0.031
`groups
`closporin
`chicle group The magnitude of improvement in the
`but not
`in the
`as larger than that
`in the velucle group at
`groups
`closporin
`time points but
`there were no statistically
`significant differ
`ences among any of the groups at any time point
`fhere were no significant within-group or betneen-group dif
`ferences in photophobia pain or burning arid stinging at an time
`point The mean scores at baselme for all
`these parameters ranged
`to mild to moderate in all
`tmeatment groups
`Baseline OSD1 scores ranged from 33 to 42 on
`scale from
`to 100 where
`indicates no disability and 100 indicates complete
`treatment groups At both treatment week 12 and
`disability in all
`week
`trend toward impmove
`there was at
`least
`posttreatment
`ment in the OSDI score in the
`clospominA 0.1% 0.2% amid 0.4%
`groups whereas there was either no change or worsening in the
`0.1% and 02%
`At seek 12 cyclospormn
`vehicle group Fig
`significantis reduced OSDI scores fP
`008 3ius decrease vias
`0.1% than with cyclo
`significantly greater with cyclosporin
`05% or 02% iP
`in 0511
`0.032 This impros ement
`period with
`scores persisted into the posttreatment
`significant
`
`all
`
`from
`
`sporin
`
`Week
`
`Wk
`
`Week
`
`12
`
`Post-Tx Wk
`
`Poet-Tx Wk
`
`0.2
`
`i.o
`
`-0.2
`
`Cs 54
`
`cx
`-t
`
`ct
`
`-0.6
`
`-1.2
`
`-1.4
`
`DVehicle CsA005% CsA0.1% tllCsAO.2%
`
`inCsAO.4%
`
`Figure
`
`Change from baseline in ocular dryness CsA tyclosporin
`0.036
`from baseline
`Significantly different
`0.010
`from vehicle
`
`significantly
`
`different
`
`971
`
`FAMY CARE - EXHIBIT 1015-0005
`
`

`

`Ophthalmology
`
`Volume 107 Number
`
`May 2000
`
`Week
`
`12
`
`Post-TX Wk
`
`Table
`
`Change in Ocular Microflora From Baseline to Week 12
`
`-c
`
`DVehiclo
`
`CsAO.O5% UCsAO.I% IIICsAO.2%
`
`unsAO4%i
`
`Figure
`
`Change
`
`from baseline
`
`in the OSDL CsA Cyclosporin
`0.026
`from baseline
`significandy different
`Significantly different
`0032
`02% iP
`005% and cyclosporin
`
`from cyclosporin
`
`02% group
`in the c5 closporin
`
`0.026
`0.1%
`
`seen
`
`imprueInent seen in the eclusporin
`and
`trend tow ard significance
`0.055
`group
`0.1% produced
`Only cyclosporin
`improvements
`significant
`froni baseline values in tear film debris at any time pomi neck
`005 week 12
`There were no significant
`0.03
`in tear break up time among the treatment groups
`differences
`At treatment week 12 and both posttreatment
`visits patients in
`greater nuInher of REFRESH units per
`the e1iicle group used
`day mean values week 12 4.3 units posttreatmenl week
`5.3
`week
`5.8 units than those in any of the
`units posttreatment
`treatment groups mean values week 12
`to
`cyclosporin
`units posttreatment week
`to 39 units pristtreatni ent
`to 3.7 units hutthis diflerence was not statistically
`
`eek
`
`significant
`
`Safety Analysis
`
`isit
`
`cyclosporin
`
`at
`
`Analy sis of blood saniples revealed that peak cy closporin
`levels
`were 0.16 ng/ml
`in all dosage groups Only five patients had
`blood levels
`trough that were greater
`than
`to 0.16 ng/ml
`the limit of detection
`for
`ng/ml
`lrange
`ng/ml
`the assay method No significant differences were noted in blood
`among any dosage treatment group at any
`concentrations
`Comparison of trough whole blood cyclosporm
`concentrations
`and end of the treatment period suggested
`between the begnming
`no substantial accumulation of cyciosporin
`after multiple ocular
`mstillations for 12 weeks
`No ocular
`infections occurred in any of the treatment groups at
`an time during the treatment or posttreatment
`periods and thei
`was no overgrowth of ocular microorgamsms with any of the
`trt.atments The microbial analysis found that
`the cyclosporin
`groups generally had fewer ocular microorganisms than the vehi
`of ii patients 82%
`cle group At week 12
`the chicle group
`culture posittie whereas 24 of 47 patients 51% weie
`were
`groups There was also
`culture positive in the cyclosporin
`species from 19 to 10 and total
`trt.nd for
`decrease in bacterial
`from 40 to 31 after 12 ireeks of
`strains of organisms recovered
`there was
`treatment whereas
`trend for an an
`cyclosporin
`creased numbei of bacterial
`and total
`species from to
`ii
`organisms from to 19 after vehicle treatment aphylococcus
`both at
`epdernidin was the organism most
`frequently isolated
`baseline and at week 12 Although there were changes in microbial
`flora during the treatment period in all patients analyzed changes
`in the amount or type of bacteria detected these changes were
`in all
`that
`comparable
`treatment groups suggesting
`transient
`in patients with dry eye
`ocular flora may be nommal
`changes
`disease Table
`
`972
`
`Number of Patients
`
`No Growth to
`Any Growth
`
`Any Growth to
`No Growth
`
`Change in
`Grams Stain
`
`Treatment
`
`Group
`
`Vehicle
`CsA 005%
`CsA 0100
`CsA 0.2e
`CiA 0.4e
`
`14
`
`15
`
`14
`
`15
`
`16
`
`CsA
`cyclosporin
`No growth to any growth
`bacteria at week 12
`
`Any growth to no growth
`bacteria at week 12
`
`no bacteria
`
`at baseline but
`
`the presence of
`
`presence of bacteria
`
`at baseline
`
`but no
`
`Change
`
`in Grams
`
`stain
`
`from grarn.neganve
`
`to grans.positivc or
`
`conversely
`
`total of 15 treatment-related ad erse ci ents were reported by
`The greatest
`the 162 patients in the intent-to-treat group Table
`mcidence of treatment-related ad erse events occurm ed in patients
`of 33 9.1% and the most
`in the vehicle
`group
`frequently
`of 162
`reported adverse event was superficial pruictate keratitis
`3% No deaths or serious treatment-related ad erse
`cuts oc
`curred in any patient during the study
`No
`in usual acuity or blood
`significant changes
`clinically
`cheniistjy and hematology values including liver and renal func
`tion parameters were obserued in any treatment gloup and no
`adverse ci ents related to blood chemrnstry or
`patients expenenced
`hematology Only one patient had
`clinically significant increase
`intraocular pressure from basehne defined as an mtraocular
`pressure that was within the normal range at baseline and increased
`to 25 innmtrg and that patient was in the uehicle group There
`were
`no statistically
`significant within-group or
`or chnically
`among-group changes in any biomieroscopic variables except at
`week
`group in which there was
`the vehicle
`significant increase from baselme in lid erythema
`
`statistically
`
`016
`
`Discussion
`
`The most
`important